Source: Health Products and Food Branch (CA) Revision Year: 2020
Patients who are hypersensitive to pantoprazole, substituted benzimidazoles, or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
Co-administration with rilpivirine is contraindicated.
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, or melena) and when gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with TECTA (pantoprazole magnesium) is instituted since treatment with pantoprazole magnesium may alleviate symptoms and delay diagnosis. Further investigation should be considered if symptoms persist despite adequate treatment. In long-term treatment, patients should be kept under regular surveillance.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
Decreased gastric acidity due to any means, including proton pump inhibitors (PPIs), increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with PPIs can lead to an increased risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.
An increased risk for Clostridium difficile infection (CDI) and Clostridium difficile-associated diarrhea (CDAD) has been observed in association with PPI use in several observational studies. CDI/CDAD should be considered in the differential diagnosis for diarrhea that does not improve. Additional risk factors for CDI and CDAD include recent hospitalization, the use of antibiotics, old age and the presence of co-morbidities.
Patients should be prescribed PPIs at the lowest dose and for the shortest duration required for the condition being treated and be reassessed to ascertain whether continued PPI therapy remains beneficial.
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. A temporary withdrawal of the PPI may be considered in some patients receiving treatments with high dose methotrexate.
Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and longterm PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosisrelated fractures should be managed according to established treatment guidelines (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).
Effects of long-term treatment include hypergastrinemia, possible enterochromaffin-like (ECL) cell hyperplasia and carcinoid formation in the stomach, adenomas and carcinomas in the liver and neoplastic changes in the thyroid.
In the rat, the mechanism leading to the formation of gastric carcinoids is considered to be due to the elevated gastrin level occurring during chronic treatment. Similar observations have also been made after administration of other acid secretion inhibitors. (For further details, see TOXICOLOGY).
Short-term and long-term treatment with pantoprazole sodium in a limited number of patients up to 6 years have not resulted in any significant pathological changes in gastric oxyntic exocrine cells.
PPIs have been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. A change in gastric pH may change the absorption of the antiretroviral drug. Other possible mechanisms are via CYP 2Cl9.
Co-administration is contraindicated due to significant decrease in rilpivirine exposure and loss of therapeutic effect (see CONTRAINDICATIONS).
Co-administration with atazanavir or nelfinavir is not recommended due to decreased atazanavir and nelfinavir exposure (see the REYATAZ and VIRACEPT Product Monographs).
If the combination of TECTA with atazanavir is judged unavoidable, close clinical monitoring is recommended in combination with the use of 400 mg atazanavir/100 mg ritonavir dose; the dose of TECTA should not exceed an equivalent dose of omeprazole of 20 mg daily (see REYATAZ Product Monograph).
If TECTA is co-administered with saquinavir/ritonavir, caution and monitoring for potential saquinavir toxicities, including gastrointestinal symptoms, increased triglycerides, deep vein thrombosis and QT prolongation, are recommended. Dose reduction of saquinavir should be considered from the safety perspective for individual patients (see INVIRASE Product Monograph).
Pantoprazole 40 mg daily is not recommended in patients with severe liver disease. For more details please see ACTION & CLINICAL PHARMACOLOGY, Special Populations & Conditions.
The daily dose used in renal insufficient patients, as a rule, should not exceed the recommended dosage regimens. See ACTION & CLINICAL PHARMACOLOGY, Special Populations & Conditions.
Pantoprazole should not be used in combination treatment for the eradication of H. pylori in patients with severe hepatic or renal dysfunction since currently no data are available on the efficacy and safety of pantoprazole in combination treatment of these patients.
Subacute cutaneous lupus erythematosus (SCLE) has been reported with the use of PPIs. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping TECTA. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).
Hypomagnesemia, symptomatic and asymptomatic, has been reported in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia. (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
The chronic use of PPIs may lead to hypomagnesemia.
The prolonged use of proton pump inhibitors may impair the absorption of protein-bound Vitamin B12 and may contribute to the development of cyanocobalamin (Vitamin B12) deficiency.
Long-term use of TECTA is associated with an increased risk of fundic gland polyps, especially beyond one year (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Most fundic gland polyps are asymptomatic. Use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
During treatment with antisecretory drugs, chromogranin A (CgA) increases due to decreased gastric acidity. Increased CgA levels may interfere with investigations for neuroendocrine tumours. To avoid this interference, TECTA treatment should be stopped 14 days before CgA measurements (see DRUG INTERACTIONS).
There are no adequate or well-controlled studies in pregnant women. Studies in animals have shown reproductive toxicity, the potential risk for humans is unknown. TECTA (pantoprazole magnesium) should not be administered to pregnant women unless the expected benefits outweigh the potential risks to the fetus. See also REPRODUCTION AND TERATOLOGY.
Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Pantoprazole should not be given to nursing mothers unless its use is believed to outweigh the potential risks to the infant. See also REPRODUCTION AND TERATOLOGY.
The safety and effectiveness of pantoprazole in children have not yet been established.
No dose adjustment is recommended based on age. The daily dose used in elderly patients, as a rule, should not exceed the recommended dosage regimens. See PHARMACOLOGY. Benefits of use of PPIs should be weighed against the increased risk of fractures as patients in this category (>71 years of age) may already be at high risk for osteoporosis-related fractures. If the use of PPIs is required, they should be managed carefully according to established treatment guidelines (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).
Pantoprazole is well tolerated. Most adverse events have been mild and transient showing no consistent relationship with treatment.
The following adverse events (the most frequently reported) have been reported in individuals receiving pantoprazole sodium therapy (40 mg once daily) in controlled clinical trials of at least 6 months duration: Headache (2.1%), Diarrhea (1.6%), Nausea (1.2%).
No differences in adverse reactions are expected between pantoprazole magnesium and pantoprazole sodium.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
In a short term study (40 mg pantoprazole magnesium tablet, once daily for 7 days) in patients with GERD, and in a 4 to 8-week clinical trial in 636 GERD patients, the adverse event profile seen with TECTA (pantoprazole magnesium) 40 mg tablet was similar to that seen with the pantoprazole sodium 40 mg tablet.
No differences in adverse reactions are expected between pantoprazole magnesium and pantoprazole sodium.
Adverse events have been recorded during controlled clinical investigations in 13000 patients exposed to pantoprazole sodium as the single therapeutic agent for treatment of conditions requiring acid suppression.
The following adverse reactions considered possibly, probably, or definitely related by the investigator have been reported in individuals receiving pantoprazole sodium therapy (20 mg or 40 mg once daily) in long-term clinical trials (duration of at least 6 months).
There were a limited number of H. pylori positive patients in these studies and therefore, definitive conclusions with regard to long-term consequences of H. pylori infection and acid suppressive treatment on gastric inflammation in this sub-group cannot be made.
Adverse drug reactions with a frequency of ≥ 1% related to 40 mg pantoprazole sodium, assessed as possibly, probably or definitely related by the investigator:
| Preferred term | Number of patients | Percentage of patients |
|---|---|---|
| Headache | 24 | 2.1 |
| Diarrhea | 18 | 1.6 |
| Nausea | 13 | 1.2 |
Adverse drug reactions with a frequency of 0.1 to 1% related to 40mg pantoprazole sodium:
Cardiovascular System: Blood Pressure Increased, Hypertension, ECG Abnormal
Gastrointestinal Disorders: Flatulence, Abdominal distension, Abdominal pain, Abdominal pain upper, Loose stools, Esophageal reflux aggravated, Gastric polyps, Abdominal discomfort, Abdominal tenderness, Constipation, Eructation, Vomiting, Dyspepsia, Gastroesophageal reflux, Esophagitis
General Disorders: Fatigue, Peripheral Edema, Pyrexia
Hepatobiliary Disorders: Alanine aminotransferase increased, Aspartate aminotransferase increased, Liver function tests abnormal, Transaminases increased
Laboratory Parameters: Hypertriglyceridemia
Metabolic and Nutritional: Appetite decreased, Weight increase
Nervous System Disorders: Dysgeusia, Dizziness, Migraine, Vertigo
Respiratory System: Cough
Skin and Subcutaneous Tissue Disorders: Pruritus, Rash
Special Senses: Mouth dry, Vision blurred
Other: Neoplasm
The following adverse reactions considered possibly, probably, or definitely related by the investigator have been reported in individuals receiving pantoprazole therapy (20 mg or 40mg pantoprazole sodium once daily) in short-term clinical trials (duration of up to 3 months).
Adverse Events with a frequency of 0.1 to 1% related to pantoprazole sodium 20mg or 40mg:
Gastrointestinal Disorders: Diarrhea, Flatulence, Nausea, Constipation, Abdominal pain
Nervous System Disorders: Headache, Dizziness
Skin and Subcutaneous Tissue Disorders: Pruritus
In addition, the following adverse events considered unrelated, or unlikely related by the investigator have been reported in individuals receiving pantoprazole sodium therapy (20 mg or 40 mg once daily) in short-term and long-term clinical trials.
Influenza like illness, Headache, Diarrhea
Bronchitis, Nausea, Back pain, Abdominal pain upper, Upper respiratory tract infection, Nonaccidental injury, Sinusitis, Abdominal pain, Dizziness, Arthralgia, Vomiting, Pharyngitis, Chest Pain, Gastroenteritis, Dyspepsia, Urinary tract infection, Eructation, Pyrexia, Cough, Depression, Hypertension, Pain in limb, Constipation, Fatigue, Operation, Neck pain, Nasopharyngitis, Alanine aminotransferase increased, Hemmorrhoids, Pain, Flatulence, Viral infection, Hypertriglyceridemia, Toothache, Hypersensitivity, Rash, Abdominal pain lower, Pneumonia, Abdominal distension, Dyspnoea, Muscle cramp, Rhinitis, Peripheral Edema, Tonsilitis, Angina Pectoris, Cholelithiasis, Sinus congestion, Influenza, Vertigo, Insomnia, Infection, Osteoarthritis, Hypercholesterolemia, Pruritus, Eczema, Sleep Disorder, Migraine, Aspartate aminotransferase increased, Hyperglycemia, Musculoskeletal discomfort, Blood triglycerides Increased, Myocardial infarction, Tendonitis, Weight increased, Rectal hemmorrhage, Cystitis, Nasal congestion, Arthritis, Contusion, Abdominal discomfort, Enteritis
Sepsis
A total of 1217 patients were treated with triple combination therapy including pantoprazole sodium and two antibiotics. Adverse events noted at a frequency of greater than or equal to 1% when pantoprazole sodium was used in combination with antibiotics for the eradication of an H. pylori infection included the following:
In combination with clarithromycin and metronidazole (n=725):
Body as a Whole: Headache (1.8%), Tiredness (1.1%)
Central and Peripheral Nervous System: Dizziness (1.4%)
Gastrointestinal: Diarrhea (4.8%), Nausea (3.7%), Upper abdominal pain (1.9%), Tongue pain (1.2%), Loose stools (1.0%), Buccal inflammation (1.0%)
Liver/Biliary: Hepatic enzymes increased (1.2%)
Special Senses: Bitter taste (4.0%), Metallic taste (2.1%)
In combination with amoxicillin and clarithromycin (n=492):
Body as a Whole: Headache (1.8%), Pain (1.0%)
Skin and Appendages: Exanthema (1.2%)
Gastrointestinal: Diarrhea (10.0%), Bitter taste (3.0%), Upper abdominal pain (1.4%), Nausea (1.2%)
Regardless of the combination regimen, the most frequently reported events were gastrointestinal system disorders, followed by autonomic nervous system disorders and “body as a whole”, or generalized disorders.
Please refer to the Hepatobiliary Disorders and Laboratory Parameters portions of the ADVERSE REACTION section, the ACTION & CLINICAL PHARMACOLOGY Special Populations & Conditions sections, and the WARNINGS & PRECAUTIONS Hepatic/Biliary/Pancreatic section.
The following adverse events were reported in post-marketing use and causal relation to pantoprazole sodium treatment could not be ruled out. As the events were reported spontaneously, no exact incidences can be provided:
Interstitial nephritis; Stevens-Johnson syndrome; Erythema multiforme; Toxic epidermal necrolysis (Lyell syndrome); Photosensitivity; Hyponatremia; Hypomagnesemia; Hypocalcemia*; Hypokalemia*; DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) (some fatal); Hepatocellular injury; Jaundice; Hepatocellular failure; Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in the case of pre-existence). Hypokinesia, Anterior ischemic optic neuropathy; Pancreatitis; Increased salivation; Speech disorder; Elevated creatine phosphokinase; Rhabdomyolysis; Alopecia; Acne; Exfoliative dermatitis; Nervousness; Tremor; Tinnitus; Paresthesia; Photophobia; Vertigo; Increased appetite; Hematuria; Impotence; Eosinophilia; Osteoporosis and osteoporosis-related fractures.
* May be related to the occurrence of Hypomagnesemia
In addition the following identified adverse drug reactions have been reported in oral pantoprazole sodium clinical trials in any indication and in any dosage:
Uncommon: Headache; Dizziness; Nausea/Vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort; Rash/Exanthema/Eruption; Pruritus; Asthenia, Fatigue and Malaise; Liver enzymes increased (transaminases, γ-GT); Sleep disorders.
Rare: Agranulocytosis; Disturbances in vision/Blurred vision; Urticaria; Angioedema; Myalgia; Arthralgia; Hyperlipidemias and lipid increases (triglycerides, cholesterol); Weight changes; Body temperature increased; Edema peripheral; Gynecomastia; Hypersensitivity (including anaphylactic reactions and anaphylactic shock); Bilirubin increased; Depression (and all aggravations); Taste disorder.
Very rare: Thrombocytopenia; Leukopenia; Pancytopenia; Disorientation (and all aggravations).
Withdrawal of long-term PPI therapy can lead to aggravation of acid related symptoms and may result in rebound acid hypersecretion.
There have been post-marketing reports of subacute cutaneous lupus erythematosus (SCLE) (See WARNINGS AND PRECAUTIONS, Immune).
There have been post-marketing reports of fundic gland polyps (FGPs) (see WARNINGS AND PRECAUTIONS, Gastrointestinal).
Pantoprazole undergoes extensive hepatic metabolism via cytochrome P450-mediated oxidation. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways which include oxidation by CYP3A4. This is followed by sulphate conjugation via a Phase II reaction (non-saturable, non-cytochrome P450 dependent). Pharmacokinetic drug interaction studies in man did not demonstrate the inhibition of the oxidative metabolism of the drug. No induction of the CYP 450 system by pantoprazole was observed during chronic administration of pantoprazole sodium with antipyrine as a marker. Pantoprazole causes long lasting inhibition of gastric acid secretion. Therefore, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of the bioavailability (e.g. ketoconazole, itraconazole, posaconazole, erlotinib).
The magnesium content of a 40 mg tablet is negligibly low and thus far below the amount of magnesium taken with food or dietary supplements. No differences in drug-drug interactions are expected between pantoprazole magnesium and pantoprazole sodium.
Pantoprazole sodium does not interact with carbamazepine, caffeine, diclofenac, naproxen, piroxicam, ethanol, glibenclamide, metoprolol, antipyrine, diazepam, phenytoin, nifedipine, theophylline, digoxin, oral contraceptives (containing levonorgestrel and ethinyl oestradiol), or cyclosporine. Concomitant use of antacids does not affect the pharmacokinetics of pantoprazole sodium.
Clinical studies have shown that there is no pharmacokinetic interaction between pantoprazole sodium and the following antibiotic combinations: metronidazole plus clarithromycin, metronidazole plus amoxicillin, amoxicillin plus clarithromycin.
In a preclinical study, pantoprazole sodium in combination therapy with various antibiotics (including tetracycline, clarithromycin, and amoxicillin) was shown to have a potentiating effect on the elimination rate of Helicobacter pylori infection. (See MICROBIOLOGY)
Although no interaction during concomitant administration of warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in INR have been reported during concomitant treatment in the post-marketing period. Therefore, in patients being treated with coumarin anticoagulants, monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.
Co-administration is contraindicated due to significant decreases in rilpivirine exposure and loss of therapeutic effect (see CONTRAINDICATIONS).
Co-administration of TECTA with atazanavir is not recommended. Concomitant administration of omeprazole (20 or 40 mg once daily) substantially reduced plasma Cmax and AUC of atazanavir in healthy volunteers administered atazanavir or atazanavir/ritonavir. (see REYATAZ Product Monograph).
Co-administration of TECTA with nelfinavir is not recommended. Concomitant administration of omeprazole (40 mg daily) with nelfinavir (1250 mg twice daily) markedly reduced the AUC and Cmax for nelfinavir (by 36% and 37%, respectively) and its active metabolite M8 (by 92% and 89%, respectively) (see VIRACEPT Product Monograph).
Co-administration of saquinavir requires caution and monitoring, along with potential dose reduction of saquinavir, due to increased saquinavir exposure and thus the risk of saquinavirrelated toxicities (see the INVIRASE Product Monograph).
Concomitant administration of omeprazole (40 mg daily) with saquinavir/ritonavir (1000/100 mg twice daily) increased saquinavir AUC by 82% and Cmax by 75%.
Consumption of food does not affect the pharmacokinetics (AUC and Cmax) of pantoprazole sodium (See HUMAN PHARMACOLOGY).
There have been reports of false-positive results in urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. To some extent, a cross-reactivity of proton pump inhibitors to the THC assay in the OnTrak TesTcard 9 has been seen, though this may not be limited to this screening test. In order to verify positive urine screening results, a confirmatory method should be considered.
During treatment with antisecretory drugs, chromogranin A (CgA) increases due to decreased gastric acidity. Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, TECTA treatment should be stopped 14 days before CgA measurements (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Pharmacodynamic Properties).
Generally, daily treatment with any acid-blocking medicines over a long time (e.g. longer than 3 years) may lead to malabsorption of cyanocobalamin caused by hypo- or achlorhydria. Rare cases of cyanocobalamin deficiency under acid-blocking therapy have been reported in the literature and should be considered if respective clinical symptoms are observed.
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